Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells

Han, Seungmin; Fink, J. Lynn; Jörg, David J.; Lee, Eunmin; Yum, Min Kyu; Chatzeli, Lemonia; Merker, Sebastian R.; Josserand, Manon; Trendafilova, Teodora; Andersson-Rolf, Amanda; Dabrowska, Catherine; Kim, Hyunki; Naumann, Ronald; Lee, Ji‐Hyun; Sasaki, Nobuo; Mort, Richard L.; Basak, Onur; Clevers, Hans; Stange, Daniel E.; Philpott, Anna; Kim, Jong; Simons, Benjamin D.; Koo, Bon–Kyoung

doi:10.1016/j.stem.2019.07.008

Cited by 105 publications

(122 citation statements)

References 49 publications

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“…The proposed framework can, in principle, be applied to any tissue dynamics in which niche signals and/or cellular proliferation is localized, leading to directional flows (42,43). On the other hand, substantial extension of the model would be necessary in the context of an "open niche," such as spermatogenesis (44) or skin homeostasis (11), where renewing cells form a two-dimensional layer of neutrally competing progenitors, thus with little in-plane cellular flows.…”

Section: Discussionmentioning

confidence: 99%

Stem cell lineage survival as a noisy competition for niche access

Corominas-Murtra

Scheele

Kishi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Understanding to what extent stem cell potential is a cell-intrinsic property or an emergent behavior coming from global tissue dynamics and geometry is a key outstanding question of systems and stem cell biology. Here, we propose a theory of stem cell dynamics as a stochastic competition for access to a spatially localized niche, giving rise to a stochastic conveyor-belt model. Cell divisions produce a steady cellular stream which advects cells away from the niche, while random rearrangements enable cells away from the niche to be favorably repositioned. Importantly, even when assuming that all cells in a tissue are molecularly equivalent, we predict a common (“universal”) functional dependence of the long-term clonal survival probability on distance from the niche, as well as the emergence of a well-defined number of functional stem cells, dependent only on the rate of random movements vs. mitosis-driven advection. We test the predictions of this theory on datasets of pubertal mammary gland tips and embryonic kidney tips, as well as homeostatic intestinal crypts. Importantly, we find good agreement for the predicted functional dependency of the competition as a function of position, and thus functional stem cell number in each organ. This argues for a key role of positional fluctuations in dictating stem cell number and dynamics, and we discuss the applicability of this theory to other settings.

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Section: Discussionmentioning

confidence: 99%

Stem cell lineage survival as a noisy competition for niche access

Corominas-Murtra

Scheele

Kishi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Upregulated gluconeogenesis, glycolysis, and mTOR signaling pathways also indicated that the SE cells were metabolically active. In a recent report by Han et al (Han et al, 2019), actively cycling stem cells were found in the isthmus of gastric glands. These cells are responsible for pit-isthmus-neck region maintenance, and expressed STMN1 and MKI67.…”

Section: Discussionmentioning

confidence: 92%

“…Checking for known markers of normal gastric stem cells such as AQP5 (Tan et al, 2020), LGR5, BHLHA15, RUNX1, SOX2, andTNFRSF19 (Phesse andSansom, 2017), their expression among the epithelial cells was minimal. We also checked STMN1 and MKI67, which have been recently reported to be upregulated by actively cycling stem cells at pit-isthmus-neck region of the gastric corpus epithelium (Han et al, 2019). We found STMN1 to be upregulated in the Stem-like Epithelial (SE) cells, while MKI67 was not.…”

Section: Identification Of Stem-like Epithelial Cells Associated Withmentioning

confidence: 83%

“…Overall, these results indicate that the SE cancer cells were not quiescent but instead were proliferative. This is uncommon for stem cells, as adult stem cells generally remain quiescent most of the time, though a population of actively cycling stem cells was recently found in the isthmus of gastric glands within the stomach corpus (Han et al, 2019;Takaishi et al, 2009).…”

Section: Identification Of Stem-like Epithelial Cells Associated Withmentioning

confidence: 99%

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Proliferative and quiescent human gastric cancer stem-like cells are associated with differential chemoresistance and patient mortality

Lee

Ang

Chevrier

et al. 2020

Preprint

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The tumor microenvironment is characterized by high cellular heterogeneity and a complex network of cell-cell communications. Analysis at the single cell level is required to dissect this complexity. Here we apply single-cell full-length transcriptome sequencing to analyze 3443 cells from paired normal-adjacent and tumor tissues of 15 gastric cancer patients with different histological profiles. Among the epithelial cells profiled, we discovered subsets of proliferative stem-like cells with upregulated pro-tumor pathways and that were associated with poorer prognosis. Stem-like cell enriched tissues also show distinct T cell populations with proportionally more TIM3+ CD8+ cells, while non-enriched tissues had proportionally more KLRC1+ CD8+ cells, offering opportunities for checkpoint inhibitor therapy. In silico predictions of ligand-receptor interactions revealed immune-suppressive interactions between these stem-like cells and immune cells via interacting pairs such as Nectin-2(CD112)-TIGIT, Galectin-9-TIM3 and CXCL16-CXCR6. Using immunohistochemistry, we found CD8+ T cells expressing TIGIT in close proximity to stem-like cells expressing NECTIN2.

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“…94 In summary, the two main locations of functional gastric stem cells are the isthmus in the corpus (oxyntic stomach) and towards the base of the antral glands. Numerous markers have been proposed to identify them 95,96 and undoubtedly many cells co-express many of them ( Figure 7). Using cell-specific drivers, it is clear that conditional activation of the likes of Kras G12D and/or inactivation of Apc are potent inducers of IGC and/or the preceding metaplasia.…”

Section: Stomachmentioning

confidence: 99%

The cellular origins of cancer with particular reference to the gastrointestinal tract

Alison

2020

Int J Experimental Path

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Summary Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric‐antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including ‘reserve’ stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar‐ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.

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Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells

Cited by 105 publications

References 49 publications

Stem cell lineage survival as a noisy competition for niche access

Stem cell lineage survival as a noisy competition for niche access

Proliferative and quiescent human gastric cancer stem-like cells are associated with differential chemoresistance and patient mortality

The cellular origins of cancer with particular reference to the gastrointestinal tract

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